While rates of heroin dependence have been fairly stable over the last several years, rates of prescription opioid abuse, dependence and diversion have risen significantly. The initial 5-year award focused on the emerging prescription opioid abuse epidemic by conducting a series of studies on the clinical pharmacology of the most widely abused opioids (hydrocodone, oxycodone and Oxycontin(R)). These studies investigated relative abuse potential estimates, relative potency, effects of pain on abuse liability, and pharmacokinetics and pharmacodynamics of these drugs when misused by the oral, intranasal and intravenous routes. The present application extends these findings by conducting a series of studies to collect new data on opioids purported to have low abuse liability but, based upon surveillance studies, are emerging as new drugs of abuse, including tramadol, buprenorphine (Subutex(R)) and buprenorphine/naloxone (Suboxone(R)). Three studies will be conducted, enrolling both sporadic opioid abusers and opioid dependent individuals, to examine the relative abuse potential and reinforcing efficacy of tramadol, buprenorphine and buprenorphine/naloxone when misused by various routes of administration. These studies include careful double-blind, randomized, placebo- controlled, crossover designs and incorporate innovative methodological additions to the standard abuse liability approach, including 1) concurrent evaluation of the direct reinforcing efficacy of these compounds using human self-administration procedures to assess the concordance of findings between the "gold standard" approach to a model that examines drug-taking behavior directly, 2) multiple relevant comparator agents, and 3) multi-dimensional outcomes of safety, subjective reports, observer-rating and psychomotor performance along. The three proposed inpatient studies will examine the comparative abuse liability and reinforcing efficacy of 1) oral tramadol over a range of doses in comparison to oxycodone (a high efficacy agonist), codeine (an intermediate efficacy agonist), and placebo in non-dependent opioid abusers, 2) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone, codeine and placebo in non-dependent opioid abusers, and 3) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone, naloxone and placebo in opioid-dependent subjects maintained on a short-acting pharmaceutical opioid. These studies will provide important new information on two emerging drugs of abuse- tramadol and buprenorphine- both drugs at risk for being rescheduled to more restrictive status in the U.S. It is critical that availability of these drugs be preserved for their target patient groups (i.e., pain patients and opioid dependent individuals seeking office- based treatment for drug dependence, respectively) while protecting the public safety. These studies will provide empirical data on the relative abuse liability of these drugs in a relevant population and can inform and support evidence-based regulatory decision-making. PUBLIC HEALTH RELEVANCE: Prescription opioid abuse has increased dramatically in the United States and is a significant public health problem. It is important to understand the pharmacological effects of prescribed opioids in order to predict and control their abuse and other negative health consequences. These studies will provide new information on the abuse-related features of tramadol (used for pain) and buprenorphine alone and in combination with naloxone (used for treatment of opioid dependence).